Enhanced therapeutic potential of adoptive immunotherapy by in vitro CD28/4-1BB costimulation of tumor-reactive T cells against a poorly immunogenic,major histocompatibility complex class I-negative A9P melanoma

Costimulation plays a critical role in T-cell activation and amplification of anti-tumor immunity. Although CD28 engagement triggers an early activati on signal, activation-induced 4-1BB molecule on T cells transmits a crucial signal for further expansion and maturation of effector cells. In this rep ort, the authors show that costimulation through CD28 and 4-1BB pathways sy nergistically enhances the therapeutic efficacy of T cells from tumor-drain ing lymph nodes. Intravenous adoptive transfer of costimulated T cells into mice bearing disseminated micrometastasis of a poorly immunogenic, major h istocompatibility complex class I-negative A9P melanoma results in a 60% cu re rate. Autopsy of mice that died after unsuccessful treatment revealed tu mor growth in the liver, spleen, and skin with minimal or no evidence of pu lmonary disease. In contrast, mice that received no treatment or noncostimu lated T cells had massive pulmonary tumors, suggesting that adoptively tran sferred T cells are less effective against growth of extrapulmonary tumors. These results show that costimulation of tumor-draining lymph node T cells through CD28 and 4-1BB increases their potential for cancer immunotherapy and suggests that improper trafficking of tumor-reactive T cells to extrapu lmonary sites must be improved to enhance clinical efficacy.